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A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon

Binita Das1,2, Beth K Neilsen1, Kurt W Fisher1,3

  • 1Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Scientific Reports
|March 2, 2018
PubMed

Insights

AMP-activated protein kinase (AMPK) subunit expression varies in colon cancer cells. Targeting AMPKα2 or inhibiting AMPK with novel compounds shows potential for colon cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor.
  • AMPK is a heterotrimer comprising α, β, and γ subunits, with varying roles in cellular processes.

Purpose of the Study:

  • To investigate the differential expression and functional significance of AMPK subunits in colon cancer.
  • To identify novel small molecules that inhibit AMPK and exhibit selective toxicity towards colon cancer cells.

Main Methods:

  • Analysis of AMPK subunit expression across diverse colon cancer cell lines.
  • siRNA-mediated depletion of AMPK subunits to assess cell viability.
  • Screening of a natural product library using Functional Signature Ontology (FUSION) to identify AMPK inhibitors.
  • Assessing the selective toxicity of identified compounds against colon cancer cells versus normal colon epithelial cells.

Main Results:

  • AMPKα1 expression is consistent, but its depletion does not cause cell death.
  • AMPKα2 expression varies, and its depletion induces cell death in specific colon cancer cell lines (SW480, HCT116).
  • FUSION identified 5'-hydroxy-staurosporine as a competitive AMPK inhibitor with preferential toxicity to colon cancer cells.

Conclusions:

  • AMPKα2 plays a critical role in colon cancer cell survival.
  • AMPK kinase inhibition represents a potential therapeutic strategy for colon cancer.
  • FUSION is a valuable platform for discovering novel small molecule inhibitors for cancer therapy development.

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